Caspofungin Acetate

Caspofungin acetate for Injection is an echinocandin antifungal indicated in adults and pediatric patients (3 months of age and older) for:

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients. ( 1 )
• Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. ( 1 )
• Treatment of esophageal candidiasis. ( 1 )
• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. ( 1 )

1.1 Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients Caspofungin acetate for Injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.1 , 14.5 )] .

1.2 Treatment of Candidemia and Other Candida Infections Caspofungin acetate for Injection is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.2 , 14.5 )] . Limitations of Use: Caspofungin acetate for Injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida .

1.3 Treatment of Esophageal Candidiasis Caspofungin acetate for Injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.3 , 14.5 )]. Limitations of Use: Caspofungin acetate for Injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC [see Clinical Studies ( 14.3 )] .

1.4 Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies Caspofungin acetate for Injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies [see Clinical Studies ( 14.4 , 14.5 )] . Limitations of Use: Caspofungin acetate for Injection has not been studied as initial therapy for invasive aspergillosis.

Caspofungin acetate for Injection, 50 mg, is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial, which contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate. Caspofungin acetate for Injection, 70 mg, is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial, which contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate.

• For Injection: 50 or 70 mg lyophilized powder (plus allowance for overfill) in a single-dose vial for reconstitution. ( 3 )

Caspofungin acetate for Injection is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions ( 6 )] .

• Caspofungin acetate for Injection is contraindicated in patients with known hypersensitivity to any component of this product. ( 4 )

• Hypersensitivity : Anaphylaxis, possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm, and cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with use of caspofungin acetate for injection. Discontinue Caspofungin acetate for Injection at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. ( 5.1 )
• Hepatic Effects : Can cause abnormalities in liver enzymes. Isolated cases of hepatic dysfunction, hepatitis, or hepatic failure have been reported. Monitor patients who develop abnormal liver enzymes for evidence of worsening hepatic function and evaluate risk/benefit of continuing Caspofungin acetate for Injection. ( 5.2 )
• Elevated Liver Enzymes during Concomitant use with Cyclosporine: Limit use to patients for whom potential benefit outweighs potential risk. Monitor patients who develop abnormal liver function tests (LFTs) during concomitant use with Caspofungin acetate for Injection. ( 5.3 )

5.1 Hypersensitivity Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin acetate for injection. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin acetate for injection [see Adverse Reactions ( 6.2 )] . Discontinue Caspofungin acetate for Injection at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment.

5.2 Hepatic Effects Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with caspofungin acetate for injection. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with caspofungin acetate for injection, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to caspofungin acetate for injection has not been established. Monitor patients who develop abnormal liver function tests during Caspofungin acetate for Injection therapy for evidence of worsening hepatic function and evaluated for risk/benefit of continuing Caspofungin acetate for Injection therapy.

5.3 Elevated Liver Enzymes During Concomitant Use with Cyclosporine Elevated liver enzymes have occurred in patients receiving caspofungin acetate for injection and cyclosporine concomitantly. Only use Caspofungin acetate for Injection and cyclosporine in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

The following serious adverse reactions are discussed in detail in another section of the labeling:

• Hypersensitivity [see Warnings and Precautions ( 5.1 )]
• Hepatic Effects [see Warnings and Precautions ( 5.2 )]
• Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Warnings and Precautions ( 5.3 )]
• Adults : Most common adverse reactions (incidence 10% or greater) are diarrhea, pyrexia, ALT/AST increased, blood alkaline phosphatase increased, and blood potassium decreased. ( 6.1 )
• Pediatric patients : Most common adverse reactions (incidence 10% or greater) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin acetate for injection cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The overall safety of caspofungin acetate for injection was assessed in 1,865 adult individuals who received single or multiple doses of caspofungin acetate for injection: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients In the randomized, double-blinded empirical therapy study, patients received either caspofungin acetate for injection 50 mg/day (following a 70 mg loading dose) or AmBisome ® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the caspofungin acetate for injection and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. Adverse reactions occurring in 7.5% or greater of the patients in either treatment group are presented in Table 2 . Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or Greater for at Least One Treatment Group Within any system organ class, individuals may experience more than 1 adverse reaction. * 70 mg on Day 1, then 50 mg once daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients. † 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients. Adverse Reactions Caspofungin Acetate for Injection * N=564 (percent) AmBisome † N=547 (percent) All Systems, Any Adverse Reaction 95 97 Investigations 58 63 Alanine Aminotransferase Increased 18 20 Blood Alkaline Phosphatase Increased 15 23 Blood Potassium Decreased 15 23 Aspartate Aminotransferase Increased 14 17 Blood Bilirubin Increased 10 14 Blood Magnesium Decreased 7 9 Blood Glucose Increased 6 9 Bilirubin Conjugated Increased 5 9 Blood Urea Increased 4 8 Blood Creatinine Increased 3 11 General Disorders and Administration Site Conditions 57 63 Pyrexia 27 29 Chills 23 31 Edema Peripheral 11 12 Mucosal Inflammation 6 8 Gastrointestinal Disorders 50 55 Diarrhea 20 16 Nausea 11 20 Abdominal Pain 9 11 Vomiting 9 17 Respiratory, Thoracic and Mediastinal Disorders 47 49 Dyspnea 9 10 Skin and Subcutaneous Tissue Disorders 42 37 Rash 16 14 Nervous System Disorders 25 27 Headache 11 12 Metabolism and Nutrition Disorders 21 24 Hypokalemia 6 8 Vascular Disorders 20 23 Hypotension 6 10 Cardiac Disorders 16 19 Tachycardia 7 9 The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin acetate for injection (35%) than in the group treated with AmBisome (52%). To evaluate the effect of caspofungin acetate for injection and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin acetate for injection (3%) than in the group treated with AmBisome (12%). Candidemia and Other Candida Infections In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin acetate for injection 50 mg/day (following a 70 mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day. Adverse reactions occurring in 10% or greater of the patients in either treatment group are presented in Table 3 . Table 3: Adverse Reactions Among Patients with Candidemia or other Candida Infections* Incidence 10% or Greater for at Least One Treatment Group Within any system organ class, individuals may experience more than 1 adverse reaction. * Intra-abdominal abscesses, peritonitis and pleural space infections. † Patients received caspofungin acetate for injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment. Adverse Reactions Caspofungin Acetate for Injection 50 mg † N=114 (percent) Amphotericin B N=125 (percent) All Systems, Any Adverse Reaction 96 99 Investigations 67 82 Blood Potassium Decreased 23 32 Blood Alkaline Phosphatase Increased 21 32 Hemoglobin Decreased 18 23 Alanine Aminotransferase Increased 16 15 Aspartate Aminotransferase Increased 16 14 Blood Bilirubin Increased 13 17 Hematocrit Decreased 13 18 Blood Creatinine Increased 11 28 Red Blood Cells Urine Positive 10 10 Blood Urea Increased 9 23 Bilirubin Conjugated Increased 8 14 Gastrointestinal Disorders 49 53 Vomiting 17 16 Diarrhea 14 10 Nausea 9 17 General Disorders and Administration Site Conditions 47 63 Pyrexia 13 33 Edema Peripheral 11 12 Chills 9 30 Respiratory, Thoracic and Mediastinal Disorders 40 54 Tachypnea 1 11 Cardiac Disorders 26 34 Tachycardia 8 12 Skin and Subcutaneous Tissue Disorders 25 28 Rash 4 10 Vascular Disorders 25 38 Hypotension 10 16 Blood and Lymphatic System Disorders 15 13 Anemia 11 9 The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with caspofungin acetate for injection (20%) than in the group treated with amphotericin B (49%). […]

Cyclosporine : In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin acetate for injection. Caspofungin acetate for injection did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin acetate for injection and cyclosporine were co-administered. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )]. Tacrolimus : For patients receiving Caspofungin acetate for Injection and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Inducers of Hepatic CYP Enzymes Rifampin : Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin acetate for injection is expected to reduce the plasma concentrations of caspofungin acetate for injection. Therefore, adult patients on rifampin should receive 70 mg of Caspofungin acetate for Injection daily and pediatric patients on rifampin should receive 70 mg/m 2 of Caspofungin acetate for Injection daily (not to exceed an actual daily dose of 70 mg) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Other Inducers of Hepatic CYP Enzymes Adults : When Caspofungin acetate for Injection is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of Caspofungin acetate for Injection should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Pediatric Patients : When Caspofungin acetate for Injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m 2 Caspofungin acetate for Injection (not to exceed an actual daily dose of 70 mg) should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .

• Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 )
• Pediatric Use : Safety and efficacy in neonates and infants less than 3 months old have not been established. ( 8.4 )
• Hepatic Impairment : Reduce dose for adult patients with moderate hepatic impairment (35 mg once daily, with a 70 mg loading dose on Day 1 where appropriate). No data are available in adults with severe impairment or in pediatric patients with any degree of hepatic impairment. ( 2.4 , 8.6 , 12.3 )

8.1 Pregnancy Risk Summary Based on animal data, Caspofungin acetate for Injection may cause fetal harm (see Data ) . There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with Caspofungin acetate for Injection use in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri- implantation loss, and incomplete ossification at multiple fetal sites when administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively ( see Data ). Advise patients of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In animal reproduction studies, pregnant rats dosed intravenously with caspofungin during organogenesis (gestational days [GD] 6 to 20) at 0.5, 2, or 5 mg/kg/day (up to 0.8 times the clinical dose based on body surface area comparison) showed increased resorptions and peri-implantation losses at 5 mg/kg/day. Incomplete ossification of the skull and torso and increased incidences of cervical rib were noted in offspring born to pregnant rats treated at doses up to 5 mg/kg/day. In pregnant rabbits treated with intravenous caspofungin during organogenesis (GD 7 to 20) at doses of 1, 3, or 6 mg/kg/day (approximately 2 times the clinical dose based on body surface area comparison), increased fetal resorptions and increased incidence of incomplete ossification of the talus/calcaneus in offspring were observed at the highest dose tested. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. In peri- and postnatal development study in rats, intravenous caspofungin administered at 0.5, 2 or 5 mg/kg/day from Day 6 of gestation through Day 20 of lactation was not associated with any adverse effects on reproductive performance or subsequent development of first generation (F1) offspring or malformations in second generation (F2) offspring.

8.2 Lactation Risk Summary There are no data on the presence of caspofungin in human milk, the effects on the breast-fed child, or the effects on milk production. Caspofungin was found in the milk of lactating, drug-treated rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Caspofungin acetate for Injection and any potential adverse effects on the breastfed child from Caspofungin acetate for Injection or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of caspofungin acetate for injection in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 3 months to 17 years of age for the following indications [see Indications and Usage ( 1 )] :

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients.
• Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.
• Treatment of esophageal candidiasis.
• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). The efficacy and safety of caspofungin acetate for injection has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of caspofungin acetate for injection to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. Caspofungin acetate for injection has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida . Caspofungin acetate for injection has also not been studied as initial therapy for invasive aspergillosis in pediatric patients. In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous caspofungin acetate for injection. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin acetate for injection in safety and efficacy studies [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.5 )] . The majority of the pediatric patients received caspofungin acetate for injection at a once-daily maintenance dose of 50 mg/m 2 for a mean duration of 12 days (median 9, range 1 to 87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin acetate for injection were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see Adverse Reactions ( 6.2 )] . Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see Warnings and Precautions ( 5.3 )] .

8.5 Geriatric Use Clinical studies of caspofungin acetate for injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), Caspofungin acetate for Injection 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology ( 12.3 )] . However, where recommended, a 70 mg loading dose should still be administered on Day 1 [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. […]

Caspofungin is an echinocandin antifungal drug [see Microbiology ( 12.4 )].